The design and development of long-acting or sustained-release delivery formulations have been the focus of considerable efforts in the pharmaceutical industry for decades. Confounding these efforts is the formation of polymorphic drug forms.
Specifically, active pharmaceutical ingredients (APIs) are often administered to patients in their solid-states. Molecular solids or solid phases have been defined in thermodynamic terms as states of matter that are uniform in chemical composition and physical state. Molecular solids can exist in crystalline or noncrystalline (amorphous) phases depending on the extent of their three-dimensional order and relative thermodynamic stability. Crystalline states are characterized by a periodic array of molecules within a three-dimensional framework, termed a lattice, which are influenced by intra- and inter-molecular interactions. Crystalline forms may also include hydrates and/or solvates of the same compound.
A given crystalline form of a particular API often constitutes an important determinant of the API's ease of preparation, hygroscopicity, stability, solubility, shelf-life, ease of formulation, rate of dissolution in the gastrointestinal tract and other fluids, and in vivo bioavailability. Choice of a crystalline form will depend on a comparison of physical property variables of the different forms. In certain circumstances, one form may be preferred for ease of preparation and stability leading to longer shelf-lives. In other cases, an alternate form may be preferred for higher dissolution rate and/or better bioavailability.
Polymorphism refers to the ability of a molecule to exist in two or more crystalline forms in which the molecules within a crystal lattice may differ in structural arrangement (packing polymorphism) and/or in conformation (conformational polymorphism). A single enantiomer of a molecule may exhibit polymorphism. Polymorphic structures have the same chemical composition but different lattice structures and/or conformations resulting in different thermodynamic and kinetic properties. Thus, in the solid phase, polymorphic forms of an API exhibit different physical, chemical and pharmacological properties, such as in solubility, stability, melting point, density, bioavailability, X-ray diffraction patterns, molecular spectra, etc. However, in liquid or gaseous phases, polymorphic forms lose their structural organization and hence have identical properties. Phase transitions from one form to another may be reversible or irreversible. Polymorphic forms that are able to transform to another form without passing through a liquid or gaseous phase, are known as enantiotropic polymorphs, whereas those that are unable to interconvert under these conditions, are monotropic.
Enantiomers of chiral APIs may crystallize in three forms: (1) a racemate form in which the crystal lattice contains a regular arrangement of both enantiomers in equal amounts; (2) enantiopure forms in which the crystal lattice contains a regular arrangement of one enantiomer and not the other and vice versa; and (3) a conglomerate form in which there is a 1:1 physical mixture of two crystal lattices, one made up of a regular arrangement of one enantiomer and the other a regular arrangement of the other enantiomer.
Nimodipine [isopropyl(2-methoxyethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate] is a member of the dihydropyridine class of drugs belonging to the calcium channel antagonist family of pharmaceutical agents. Nimodipine is manufactured and marketed by Bayer AG as Nimotop™. Unsymmetrical esters of 1,4-dihydropyridine 3,5-dicarboxylic acids, processes and use as coronary and antihypertensive agents are disclosed in U.S. Pat. No. 3,799,934, incorporated herein by reference. Pharmaceutical compositions comprising nimodipine and an inert non-toxic carrier are disclosed for example in U.S. Pat. No. 3,932,645, incorporated herein by reference. When formulated as a flowable pharmaceutical composition for sustained release comprising a carrier comprising a plurality of microparticles, such that the nimodipine is dispersed throughout each microparticle, for surgical injection it is known as NimoGel™
Nimodipine can exist in amorphous or crystalline forms depending on treatment and storage conditions. Two distinct crystal forms of Nimodipine have been identified: Form I, which is the racemic crystal form with a lattice containing equal amounts of the two opposite enantiomers; and Form II, which is the conglomerate form, a 1:1 mixture of two crystal lattices, one containing one enantiomer and the other containing the opposite enantiomer (U.S. Pat. No. 5,599,824, incorporated herein by reference; Grunenberg, A. et al., “Polymorphism in binary mixtures, as exemplified by nimodipine”, International Journal of Pharmaceutics, (1995), 118: 11-21; Grunenberg, A. et al., “Theoretical derivation and practical application of energy/temperature diagrams as an instrument in preformulation studies of polymorphic drug substances”, International Journal of Pharmaceutics, (1996), 129: 147-158; Docoslis, A. et al., “Characterization of the distribution, polymorphism, and stability of nimodipine in its solid dispersions in polyethylene glycol by micro-Raman spectroscopy and powder X-ray diffraction”, The AAPS Journal, 2007, 9(3): Article 43). Nimodipine Form I melts at +124° C. and Nimodipine Form II melts at +116° C. At +25° C. and +37° C., Form II has lower solubility but higher stability when compared to Form I. Form I can transform to Form II when stirred at room temperature to +80° C.
Nimodipine has been indicated for use in neurological conditions such as aneurysms, subarachnoid hemorrhage, neuropathic pain, arthritis, etc. It is currently used in the U.S. to treat subarachnoid hemorrhage and migraine. Due to low solubility, nimodipine is only administered as oral soft-gels, commercially sold as Nimotop™. Despite its high permeability, oral administration of nimodipine is associated with lower bioavailability due to slow dissolution in gastrointestinal fluids and/or cytochrome P450 digestion. Due to limited stability and bioavailability, patients need to be administered one or two 30 mg capsules of Nimotop™ up to six times a day, causing significant inconvenience to subarachnoid hemorrhage patients who are frequently fed through tubes because they are unable to swallow due to their neurological injury. In addition, as calcium channel antagonists, IV formulations of nimodipine cannot be used because of the high risk of inducing hypotension. Various controlled release and combinatorial formulations of nimodipine, for example, for immediate release (within 0-12 hours of administration) or slower release (within 12-24 hours) of administration are disclosed, for example, in US Patent Publication No. US 2010/0215737, US 2010/0239665, etc.
The commercial available nimodipine exists primarily as Form I. An orally administered immediate release formulation containing a co-precipitate of essentially amorphous nimodipine with poly-vinyl-pyrrolidone (PVP) is described in U.S. Pat. No. 5,491,154. A pharmaceutical preparation containing a suspension of a mixture of nimodipine Form II crystals in a suspension solution is described in U.S. Pat. No. 5,599,824. A solid dispersion of nimodipine Form II in PVP with fast release kinetics is described in Papageorgiou, G. Z. et al., “The effect of physical state on the drug dissolution rate: Miscibility studies of nimodipine with PVP”, Journal of Thermal Analysis and Calorimetry, 2009, 95(3): 903-915.
Thus the formation of different polymorphic drug forms in a microparticle can impact product performance and stability. What are needed are formulation strategies that can control to formation of drug polymorphs. These needs and other needs are satisfied by the delivery systems and methods of the present invention. Additionally, the present invention describes sustained release microparticle formulations of nimodipine polymorphs with delayed release kinetics and improved stability.